Our initial work on ALS was a case-control study conducted in New England in 1993-96. Specific aims were to characterize potential associations of ALS with (i) lead exposure; (ii) exposure to other neurotoxicants, eg, mercury, solvents and pesticides; (iii) lifestyle factors such as cigarette smoking and diet; and (iv) genetic polymorphisms affecting neurologic function or lead metabolism. Cases (N=110) were recruited at two hospitals in Boston, MA. Population controls (N=256) identified by random digit dialing were frequency matched to cases by age, sex, and region of residence within New England. We collected information on occupational, residential, and recreational exposure to lead using a structured interview. In addition, we measured blood and bone lead levels, the latter using in vivo K x-ray fluorescence (K-XRF), and archived whole blood and serum samples for studies of gene-environment interaction. Initial analyses from this study focused on the relationship of ALS to lead exposure. We found that ALS risk was associated with a 1.9-fold increase in self-reported occupational exposure to lead, with a dose-response for lifetime days of lead exposure. ALS risk was also associated with elevations in both blood and bone lead levels: it was increased 1.9-fold for each mg/dl increase in blood lead, 3.6-fold for each doubling of patella lead, and 2.3-foldfor each doubling of tibia lead. These results extended previous reports based entirely on interview data, showing for the first time an association of ALS with lead biomarkers. In other analyses, we found that ALS was associated with cigarette smoking but not alcohol use or diet, with family history of ALS, and with head injury. In analyses of genetic susceptibility, we found that ALS was associated with polymorphisms in ALAD but not VDR; neither gene modified the association of lead with ALS. We also found that ALS was associated with the VEGF promoter region but not with XRCC1. We studied survival in ALS using information on date and cause of death retrieved from the National Death Index. Median survival from diagnosis to death was 28 months. Shorter survival was associated with older age at diagnosis, female sex, bulbar onset, shorter interval between symptom onset and diagnosis, and reduced lung function. Shorter survival from diagnosis to death had a weak inverse association with blood lead (hazard ratio = 0.9; 95% confidence interval, 0.8-1.0) and a stronger inverse association with patella lead (0.5; 0.2-1.0) and tibia lead (0.3; 0.1-0.7); similar results were found for survival from symptom onset to death. These unexpected results suggest that lead exposure is associated with longer survival in ALS cases and, if confirmed, may shed light on mechanisms involved in disease progression. More recently, we have studied ALS using several new data sources. We used data from the Agricultural Health Study to conduct a prospective analysis of ALS and pesticide exposure. We found that although ALS was not associated with overall pesticide exposure, it was associated with use of several organochlorine insecticides (1). The similarity of these results with findings for Parkinson's disease suggests that organochlorine compounds may play an important role in the pathophysiology of neurodegenerative disease. We are collaborating with researchers at Duke University Medical School and the Durham Veterans Administration Hospital on a case-control study of ALS in US military veterans. The study, Genes and Environment in Veterans with ALS (GENEVA), enrolled 670 cases from the VA ALS registry and 1000 matched veteran controls and collected extensive interview data and DNA samples. We conducted an add-on biomarker substudy, collecting blood samples for measurement of heavy metals. In an analysis of 184 ALS cases and 194 matched controls, we found that a doubling of blood lead was associated with a 1.9-fold increase in ALS risk, a result both qualitatively and quantitatively similar to our finding from the New England study. These results extend our previous work by incorporating adjustment for bone turnover biomarkers into the analysis. The finding that the association of blood lead with ALS risk persists after such adjustment strongly suggests that the association is not a consequence of increased bone turnover among cases, who may be less active than controls. We plan to continue analysis of data from the biomarker substudy, to examine associations of lead with ALS survival, associations of other metals with ALS risk, and the influence of genetic variation. In addition, we now have the opportunity to take the lead on analyses of questionnaire data from the GENEVA study as a whole. In the past year we have begun coding occupational histories and established a collaboration with an industrial hygienist to evaluate exposures based on these histories. Our collaboration with Duke and the Durham VA also involved participation in a large high-density genome-wide association (GWA) screen of genetic data from the entire population of ALS cases in the VA Registry (2). Although no SNPs reached genome-wide significance in the discovery phase for either phenotype, three SNPs were statistically significant in the replication analysis of ALS outcome: rs6080539 (177 kb from PCSK2), rs7000234 (4 kb from ZNF704), and rs3113494 (13 kb from LOC100506746). Two SNPs located in genes that were implicated by previous GWA studies of ALS were marginally significant in the pooled analysis of discovery and replication samples: rs17174381 in DPP6 (p&#8202;=&#8202;4.410(-4)) and rs6985069 near ELP3 (p&#8202;=&#8202;4.810(-4)). Our results underscore the difficulty of identifying and convincingly replicating genetic associations with a rare and genetically heterogeneous disorder such as ALS, and suggest that common SNPs are unlikely to account for a substantial proportion of patients affected by this devastating disorder. We are collaborating with researchers from the Karolinska Institute on studies based on Swedish registries. In one, we found that both low and high maternal age were associated with 1.5- to 1.7-fold increase in ALS risk. Further, ALS risk was slightly greater in individuals with more younger siblings, particularly if the latter were born after an interval of at least six years (1.8-fold increase). These results provided some support for the theory that early life exposures might contribute to disease pathogenesis. In a second study, we provided quantitative data on familial risk of ALS, showing that risk was increased 17-fold in siblings of ALS cases and 9-fold in their children. Although increased risk among families of ALS cases is well-established, these quantitative data suggest a strong genetic component to the disease. Another study investigated the relationship of ALS to sepsis and CNS infections, finding that neither increased ALS risk but that sepsis was increased after diagnosis (3). We are continuing our collaboration with the Karolinska, using the Swedish registries to study the association of ALS with prior medical conditions including osteoporosis/fractures and diabetes.